Genetic variation that alters activity-dependent circuit formation may contribute to an experience-dependent imbalance in circuit development. Brain derived neurotrophic factor (BDNF) is a neurotrophic factor involved in developmental maturation of neural processes and cell survival. 20-30% of Caucasians carry a polymorphism in the BDNF gene, where codon 66 is altered from a valine to methionine (Shimizu et al., 2004), a change which has been shown to alter activity regulated release of BDNF (Chen et al., 2006). The BDNF val66met polymorphism has been linked to anxiety and depression (although not without controversy), with stronger correlation in persons who have had the greatest amount of early life stress (Gatt et al., 2009). We hypothesize that individuals possessing the met66 allele of BDNF have weakened parahippocampal inputs to the cingulated and that early life stress enhances amygdala inputs to the cingulated. We hypothesize an imbalance in projections to the frontal cortex biases emotional experience and behaviors. In our animal model of this process, underdevelopment of the (parahippocampal) perirhinal (PRH) cingulated afferents enable enhanced, competitive development of the basolateral amygdala (BLA) cingulated afferents leading to abnormal dominance of harm avoidance information in frontal circuits involved in action selection and cognitive control. We propose a PRH:BLA cingulated projection imbalance, with diverse causes, may underlie a range of disorders in the spectrum of anxiety and novelty seeking. We will test the hypothesis that BDNF met66 variant mice which show enhance anxiety (Chen et al. 2006) also show unbalanced development of PRH and BLA inputs to the cingulated cortex. To pursue this putative endophenotype of anxiety, we will use state of the art longitudinal in vivo imaging of synapse formation (Aim 1) and optogenetic tools (Aim 2) to probe the adolescent development of long range afferents from the PRH and BLA to the cingulated cortex in BDNF val66met knocking mice (Chen et al., 2006). Specific measures will include in vivo cingulated spine and PRH and BLA bouton turnover and density (Aim 1), the ratio of excitatory and inhibitory currents driven by the BLA and PRH afferents in the cingulated, and the average PRH- and BLA-cingulated AMPA:NMDA ratio (Aim 2). We will also investigate the effects adolescent stress and cognitive training on plasticity (Aim 1) and connectivity (Aim 2) of PRH and BLA afferents. We predict that cognitive training in tasks that engage the PRH and the cingulated together will protect against the development of PRH:BLA imbalance and reduce anxiety behavior. Our experiments will inform understanding of the developmental etiology of disorders of anxiety and harm avoidance, provide an endophenotype that may be transferred to human studies, and test forms of cognitive therapy to rebalance circuit development.
Excess anxiety or its opposite, low harm avoidance, can profoundly disrupt human lives. In our model, abnormal juvenile development leads to a lack of balance in inputs that relay information about safety and danger to the frontal cortex adversely affecting decision making. We will test this model to illuminate the developmental causes of disorders of anxiety and harm avoidance, provide a biological measure that can be transferred to human studies, and test forms of cognitive therapy to repair an imbalance in these circuits.
|Johnson, Carolyn M; Peckler, Hannah; Tai, Lung-Hao et al. (2016) Rule learning enhances structural plasticity of long-range axons in frontal cortex. Nat Commun 7:10785|
|Johnson, Carolyn M; Loucks, F Alexandra; Peckler, Hannah et al. (2016) Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence. Dev Cogn Neurosci 18:113-20|
|Piekarski, David J; Johnson, Carolyn M; Boivin, Josiah R et al. (2016) Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? Brain Res :|
|Thomas, A Wren; Caporale, Natalia; Wu, Claudia et al. (2016) Early maternal separation impacts cognitive flexibility at the age of first independence in mice. Dev Cogn Neurosci 18:49-56|
|Vandenberg, Angela; Piekarski, David J; Caporale, Natalia et al. (2015) Adolescent maturation of inhibitory inputs onto cingulate cortex neurons is cell-type specific and TrkB dependent. Front Neural Circuits 9:5|
|Boivin, Josiah R; Piscopo, Denise M; Wilbrecht, Linda (2015) Brief cognitive training interventions in young adulthood promote long-term resilience to drug-seeking behavior. Neuropharmacology 97:404-13|
|Lee, A M; Tai, L-H; Zador, A et al. (2015) Between the primate and 'reptilian' brain: Rodent models demonstrate the role of corticostriatal circuits in decision making. Neuroscience 296:66-74|
|Lee, A Moses; Hoy, Jennifer L; Bonci, Antonello et al. (2014) Identification of a brainstem circuit regulating visual cortical state in parallel with locomotion. Neuron 83:455-66|
|Tai, Lung-Hao; Lee, A Moses; Benavidez, Nora et al. (2012) Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value. Nat Neurosci 15:1281-9|
|Johnson, Carolyn; Wilbrecht, Linda (2011) Juvenile mice show greater flexibility in multiple choice reversal learning than adults. Dev Cogn Neurosci 1:540-51|